Pyridine derivatives



Patented Sept. 21, 1954 UNITED STATES PATENT OFFICE PYRIDINE DERIVATIVESHerman Herbert Fox, Passaic, N. J., assignor to, Hofimann-La Roche Inc.,Nutley, N. .L, a corporation of New Jersey No Drawing. ApplicationNovember 3, 1951,

Serial No. 254,802 r C ONHNHR In the above formula It stands for analiphatic carboxylic acid acyl, e. g., alkanoyl, substituted alkanoyl,alkenoyl, and substituted alkenoyl; and an aromatic carboxylic acidacyl, e. g., benzoyl and substituted benzoyl.

The new compounds are useful in the field of therapeutics, and moreparticularly are useful as antituberculosis agents. In general, they canbe prepared by reacting isonicotinylhydrazine (alternatively known asisonicotinic acid hydrazide) with the anhydrides or acyl halides ofaliphatic carboxylic acids and aromatic carboxylic acids to form thecorresponding 1-isonicotiny1-2-acylhydrazines. According to anotherprocedure, the compounds can be prepared by reacting isonicotinylchloride or its hydrochloride with the corresponding acyl hydrazines,which can be represented by the formula HzNNHR, R having the samemeaning already assigned thereto.

The following examples will serve to illustrate the preparation of thecompounds comprising the invention.

Example 1 To 15 grams of acetic anhydride were added, portionwise, withshaking, 14 grams of isonicotinylhydrazine. The mixture was then heatedon a steam bath for 15 minutes, and finally treated with an excess ofether, whereupon lisonicotinyl-Z-acetylhydrazine precipitated. It wasfiltered ofi and upon recrystallization from ethyl acetate, the compoundmelted at 161 C.

Example 2 30 cc. of propionic anhydride and 20 grams ofisonicotinylhydrazine were reacted in accordance Claims. (Cl. 260-295)with the procedure described in Example 1. The precipitate obtained wasl-isonicotinyl-Z-propionylhydrazine, which, upon recrystallization fromethyl acetate, melted at 1305-1315 C.

Example 3 To a refluxing solution of 20 grams of isonicotinylhydrazinein 250 cc. of dry dioxane were added, dropwise, 15.5 grams of butyrylchloride in 15 cc. of dioxane. After the addition was complate, themixture was refluxed for about 10 more minutes and then permitted tostand for about one hour. The precipitate was filtered off, washed withether, dried, and then dissolved in a slight excess of concentratedammonium hydroxide. The alkaline solution was evaporated to drynessunder vacuum and the residue was extracted several times withhotchloroform. The chloroform extracts were combined and filtered, and thechloroform was evaporated off, leaving a deposit of1-isonicotinyl-2-butyrylhydrazine which, upon recrystallization fromethyl acetate, melted at 139-139.5 C.

The 1-isonicotinyl-2-butyrylhydrazine was also prepared by reacting 20grams of isonicotinylhydrazine and 35 cc. of butyric anhydride by thesame procedure as described in Example 1.

Emample 4 A mixture of 30 grams of isonicotinylhydrazine, 22 grams ofmaleic anhydride, and 300 cc. of dioxane was heated on a steam bath forone-half hour. 1 isonicotinyl 2 (c carboxyacrylyl) hydrazineprecipitated and was recovered by filtration.

Example 5 To a solution of 35 grams of benzoic acid anhydride and 300cc. of dioxane were added 20 grams of isonicotinylhydrazine, and themixture was heated on a steam bath for about one-half hour.1-isonicotinyl-2-benzoy1hydrazine precipitated. The mixture was cooledto room temperature and the 1-isonicotiny1-Z-benzoylhydrazine wasfiltered off. Upon recrystallization from methanol, it was obtained inthe form of fine white needles, melting at 227.5228.5 0.

Example 6' 30 grams of isonicotinylhydrazine and 32.5 grams of phthalicanhydride were reacted by the same procedure as described in Example 5to yield 1-isonicotinyl-2- (o-carboxybenzoyl) hydrozine in the form ofwhite crystals, which melted at 178.5 C. Five grams ofl-isonicotinyl-Z-(ocarboxybenzoyl) hydrazine were heated at 200-- 3 220C. for 1530 minutes, and the melt was permitted to cool, whereupon asolid substance was obtained, which, upon recrystallization fromisopropanol, melted at 2235-2255 C. The compound analyzed for theempirical formula C14H903N3.

Example 7 To a mixture of 13.7 grams isonicotinylhydrazine in 100 cc.dry dioxane heated on a steam bath under reflux was added dropwise asolution of 30.2 grams of stearoyl chloride in 200 cc. benzene.Immediate precipitation took place, and the thick mass was heated. forabout an hour after addition was completed. The mixture was then cooled,filtered, and the solid was suspended in about 300 cc. of 3 N ammoniumhydroxide. The suspension was filtered, and the solid product wasrecrystallized from isopropanol to give white needles of 1 isonicotinyl2 stearoylhydrazine which melted at 125-126 C.

Example 8 A mixture of 4.8 grams 1-isonicotinyl-2-(p-car- 4 boxyacrylyl)hydrazine and 150 cc. of methanol was treated with hydrogen at about p.s. i. and C. in the presence of mg. of finely divided platinum catalyst.When the theoretical quantity of hydrogen had been taken up, themethanol was removed and the product was recrystallized from water.. The1-'-isonicotinyl-2-(B- carboxypropionyl)hydrazine was obtained in theform of fine white needles which melted at 223.5- 224.5 C.

Iclaim:

1. 1 isonicotinyl 2 acyl hydrazines, wherein the acyl radical is amember of the class consisting of alkan'oyl, carboxyalkanoyl, alkenoyl,carboxalkenoyl, benzoyl, and carboxybenzoyl radica-ls.

2. 1 isonicotinyl 2 acyl hydrazines, wherein the acyl radical is acarboxybenzoyl radical.

3. l isonicotinyl 2 acyl-hydrazines, wherein the acyl radical is acarboxyalkenoyl radical.

4. 1-isonicotinyl-2 alkanoyl hydrazines.

5. 1-isonicotinyl2-acetylhydrazine. i 6. 1; isonicotinyl 2 (ocarboxybenzoyli hydrazine.

7. 1 e isonicotinyl 2 8 carboxyacryly1)-' hydrazine. V

8. 1*isonic0tinyl-2-palmitoyl-hydrazine. 9. 1-isonicotinyl 2stearoyl-hydrazine.

10. 1-is0nicotinyl-2 benzoylhydrazine.

References Cited in the file of this patent Gautier: Chem. Abst. (1946),vol. 40, p. 3118;

Graf 3 Journal fur Prakti'sche Chemie (1933), vol. 138, pp. 289-91.

Taylor et al.: Org. Chem. of Nitrogen (1942), P. 522.

Fieser et 21.: Org. Chem. (1944), p. 32.

1. 1- ISONICOTINYL - 2 - ACYL - HYDRAZINES, WHEREIN THE ACRY RADICAL ISA MEMBER OF THE CLASS CONSISTING OF ALKANOYL, CARBOXYALKANOYL, ALKENOYL,CARBOXALKENOYL, BENZOYL, AND CARBOXYBENZOYL RADICALS.